1-Hydroxybenzotriazole → racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzylamide

HRID 220595

Reaction equation

HRID 220595 reaction equation
[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:66]3[C:71]([C:72]4[CH:79]=[CH:78][C:75]([CH2:76][NH2:77])=[CH:74][CH:73]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:62][CH2:61]2)[CH:55]=[N:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:61][CH2:62][N:63]([C:66]3[C:71]([C:72]4[CH:73]=[CH:74][C:75]([CH2:76][NH:77][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])=[CH:78][CH:79]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:64][CH2:65]2)[CH:55]=[N:54]1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 4661317(R)-Tetrahydro-3-furoic acidHCID 593220094-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzylamine

Product 1

HCID 59322067racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzylamideYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Dissolve racemic tetrahydro-furan-3-carboxylic acid (0.067 g, 0.58 mmol) in methylene chloride (5 mL). Add benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.453 g, 0.87 mmol). Add 1-hydroxybenzotriazole (0.118 g, 0.87 mmol). Add 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.24 g, 0.63 mmol) dissolved in methylene chloride (5 mL). Stir at rt for 5 min. Add diisopropylethylamine (0.113 g, 0.87 mmol). Stir at rt for 4 hr. Purify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate) to give racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamide (0.107 g, 39%). MS (ES): m/z=476.3[M+H]. Dissolve this racemate (0.107 g, 0.23 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.23 mmol, 0.23 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.110 g, 94%). MS (ES): m/z=476.3 [M+H].

Workup

  1. stirringStir at rt for 4 hr
  2. customPurify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate)

Sources & evidence

ORD record
ord-3ac4d49f4e924d3e9f8429bedab09bc8
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Linked notes

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